How antigens (and pathogens) enter the B cell follicles of secondary lymphoid tissues and are acquired by B cells has been a long-standing enigma. However, recent papers have identified at least two major pathways in which lymph-borne antigens enter the B cell area and are either acquired by cognate B cells or retained on follicular dendritic cells (FDC). Importantly, the nature of the antigen is a major factor. While small soluble antigens enter via a network of conduits formed by fibroblast reticular cells, larger protein immune complexes and particulate antigens are bound by subcapsular sinus macrophages and shuttled to the underlying B cells where they are captured by cognate B or bound by naive B cells via CD21 receptor. How the antigen is transferred to the FDC remains unclear. Most recently, we reported a third pathway in which lymph-borne influenza (uv-inactivated) was bound by dendritic cells (DC) residing in the medullary region of the LN. Capture is dependent on MBL and the C-type lectin receptor SIGN-R1. Tracking of the virus in vivo suggests DC transport virus to the B cell area. Whether the virus is handed off directly to FDC or to other intermediates in the follicles is not known. The overall goal of this revised proposal is to clarify how B cell antigen is delivered and off-loaded onto the FDC surface. Three aims are proposed: (1) B cell delivery of antigen to FDC;(2) DC transport of antigen to B cell follicles (3) Functional importance of FDC in humoral immunity. PUBLIC HEALTH RELEVANCE: Understanding where and how B cells acquire cognate antigen is of fundamental importance from both the point of view of host protection and autoimmunity. The ability to observe antigen draining into LNs directly and to determine how they are eventually acquired in real time by B cells provides a novel insight unattainable by traditional immunization methods. From a practical view, this approach could be used to develop more efficient vaccines by targeting pathogens to a specific site within the LN or spleen. Alternatively, knowledge of the pathways could be used to design inhibitors of chronic autoimmune disease.